MDM2

MDM2 proto-oncogene, the group of Ring finger proteins|Zinc fingers RANBP2-type

Basic information

Region (hg38): 12:68808176-68845544

Links

ENSG00000135679 ∙ NCBI:4193 ∙ OMIM:164785 ∙ HGNC:6973 ∙ Uniprot:Q00987 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• lessel-kubisch syndrome (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Lessel-Kubisch syndrome	AR	Renal	Among other features, the condition may involve renal failure associated with severe hypertension, and awareness may allow early diagnosis and management	Craniofacial; Dermatologic; Endocrine; Renal	28846075

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MDM2 gene.

• Accelerated tumor formation, susceptibility to (128 variants)
• Inborn genetic diseases (4 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MDM2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	24	2	27
missense			62			62
nonsense						0
start loss						0
frameshift						0
inframe indel			2			2
splice donor/acceptor (+/-2bp)			1			1
splice region			4	9	1	14
non coding			1	12	9	22
Total	0	0	67	36	11

Variants in MDM2

This is a list of pathogenic ClinVar variants found in the MDM2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-68808384-A-G		Accelerated tumor formation, susceptibility to	Benign (Dec 06, 2023)
12-68808494-A-G		Accelerated tumor formation, susceptibility to	Uncertain significance (Jun 14, 2023)
12-68808496-T-G		Accelerated tumor formation, susceptibility to	Uncertain significance (Sep 15, 2022)
12-68808546-C-T		Accelerated tumor formation, susceptibility to	Benign (Oct 01, 2020)
12-68808776-G-C		Accelerated tumor formation, susceptibility to	Benign (Nov 08, 2022)
12-68808800-T-G		Accelerated tumor formation, susceptibility to	Benign (Dec 06, 2023)
12-68809191-CT-C		Accelerated tumor formation, susceptibility to	Benign (Sep 09, 2022)
12-68809191-C-CT		Accelerated tumor formation, susceptibility to	Benign (Oct 04, 2022)
12-68809197-T-C		Accelerated tumor formation, susceptibility to	Likely benign (Apr 14, 2023)
12-68809206-A-G		Accelerated tumor formation, susceptibility to	Uncertain significance (Jul 19, 2022)
12-68809237-C-T		Accelerated tumor formation, susceptibility to	Uncertain significance (Sep 03, 2023)
12-68809239-A-G		Accelerated tumor formation, susceptibility to	Uncertain significance (May 03, 2021)
12-68809243-A-G		Accelerated tumor formation, susceptibility to	Uncertain significance (Feb 01, 2023)
12-68809249-C-T		Accelerated tumor formation, susceptibility to • not specified	Uncertain significance (Dec 19, 2023)
12-68809249-CTGT-C		Accelerated tumor formation, susceptibility to	Uncertain significance (Sep 11, 2023)
12-68809278-G-A		Accelerated tumor formation, susceptibility to	Uncertain significance (Jan 28, 2022)
12-68809281-C-A		Accelerated tumor formation, susceptibility to	Uncertain significance (May 07, 2022)
12-68809284-G-C		Accelerated tumor formation, susceptibility to	Uncertain significance (Jul 29, 2021)
12-68809296-AGTATTTTT-A		Accelerated tumor formation, susceptibility to	Likely benign (Oct 06, 2021)
12-68809299-AT-A		Accelerated tumor formation, susceptibility to	Benign (Aug 26, 2022)
12-68809300-T-C		Accelerated tumor formation, susceptibility to	Likely benign (Feb 03, 2022)
12-68809304-TG-T		Accelerated tumor formation, susceptibility to	Likely benign (Jun 24, 2021)
12-68809306-T-G		Accelerated tumor formation, susceptibility to	Likely benign (Aug 24, 2022)
12-68809309-C-T		Accelerated tumor formation, susceptibility to	Likely benign (Sep 27, 2022)
12-68813544-C-A		Accelerated tumor formation, susceptibility to	Benign (Jan 30, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MDM2	protein_coding	protein_coding	ENST00000462284	11	37259

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.000188	124791	0	3	124794	0.0000120

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.33	150	255	0.589	0.0000119	3288
Missense in Polyphen		76	148.5	0.51178		1912
Synonymous	0.596	81	88.1	0.919	0.00000424	880
Loss of Function	4.81	1	28.9	0.0346	0.00000148	359

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000290	0.0000290
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000179	0.0000177
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as a ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and SNAI1 and promotes them to proteasomal degradation (PubMed:12821780, PubMed:15053880, PubMed:15195100, PubMed:15632057, PubMed:16337594, PubMed:17290220, PubMed:19098711, PubMed:19219073, PubMed:19837670, PubMed:19965871, PubMed:20173098, PubMed:20385133, PubMed:20858735, PubMed:22128911). Ubiquitinates DCX, leading to DCX degradation and reduction of the dendritic spine density of olfactory bulb granule cells (By similarity). Ubiquitinates DLG4, leading to proteasomal degradation of DLG4 which is required for AMPA receptor endocytosis (By similarity). {ECO:0000250|UniProtKB:P23804, ECO:0000269|PubMed:12821780, ECO:0000269|PubMed:15053880, ECO:0000269|PubMed:15195100, ECO:0000269|PubMed:15632057, ECO:0000269|PubMed:16337594, ECO:0000269|PubMed:17290220, ECO:0000269|PubMed:19098711, ECO:0000269|PubMed:19219073, ECO:0000269|PubMed:19837670, ECO:0000269|PubMed:19965871, ECO:0000269|PubMed:20173098, ECO:0000269|PubMed:20385133, ECO:0000269|PubMed:20858735, ECO:0000269|PubMed:22128911}.
• Disease: DISEASE: Note=Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding.
• Pathway: PI3K-Akt signaling pathway - Homo sapiens (human);Chronic myeloid leukemia - Homo sapiens (human);Melanoma - Homo sapiens (human);Bladder cancer - Homo sapiens (human);Cell cycle - Homo sapiens (human);Endocytosis - Homo sapiens (human);p53 signaling pathway - Homo sapiens (human);Ubiquitin mediated proteolysis - Homo sapiens (human);FoxO signaling pathway - Homo sapiens (human);Glioma - Homo sapiens (human);Thyroid hormone signaling pathway - Homo sapiens (human);Prostate cancer - Homo sapiens (human);C-type lectin receptor signaling pathway - Homo sapiens (human);Proteoglycans in cancer - Homo sapiens (human);MicroRNAs in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Viral carcinogenesis - Homo sapiens (human);Transcriptional misregulation in cancer - Homo sapiens (human);Cellular senescence - Homo sapiens (human);Epstein-Barr virus infection - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);IGF-Ncore;EGF-Ncore;Cell Cycle;Androgen receptor signaling pathway;miRNA Regulation of DNA Damage Response;TP53 Network;Signaling Pathways in Glioblastoma;Retinoblastoma (RB) in Cancer;Integrated Lung Cancer Pathway;Apoptosis;JAK-STAT;Bladder Cancer;Copper homeostasis;Apoptotic Signaling Pathway;Regulation of TP53 Expression and Degradation;ESC Pluripotency Pathways;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;miRNA regulation of prostate cancer signaling pathways;miRNA regulation of p53 pathway in prostate cancer;PI3K-Akt Signaling Pathway;G1 to S cell cycle control;Tryptophan metabolism;Senescence and Autophagy in Cancer;ErbB Signaling Pathway;DNA Damage Response;DNA Damage Response (only ATM dependent);Regulation of RUNX3 expression and activity;Disease;Signal Transduction;Gene expression (Transcription);Transcriptional regulation by RUNX3;hypoxia and p53 in the cardiovascular system;tumor suppressor arf inhibits ribosomal biogenesis;sumoylation by ranbp2 regulates transcriptional repression;hiv-1 nef: negative effector of fas and tnf;ctcf: first multivalent nuclear factor;Generic Transcription Pathway;Oncogene Induced Senescence;Oxidative Stress Induced Senescence;Cellular Senescence;SUMOylation of transcription factors;Cellular responses to stress;Post-translational protein modification;SUMO E3 ligases SUMOylate target proteins;Metabolism of proteins;RNA Polymerase II Transcription;Stabilization of p53;p53-Dependent G1 DNA Damage Response;p53-Dependent G1/S DNA damage checkpoint;G1/S DNA Damage Checkpoints;Cell Cycle Checkpoints;p73 transcription factor network;Neuronal System;AndrogenReceptor;ErbB4 signaling events;Aurora A signaling;SUMOylation;cell cycle: g2/m checkpoint;Cellular responses to external stimuli;p53 signaling pathway;atm signaling pathway;Glucocorticoid receptor regulatory network;Ub-specific processing proteases;Validated transcriptional targets of TAp63 isoforms;Regulation of TP53 Degradation;Regulation of TP53 Expression and Degradation;PIP3 activates AKT signaling;Deubiquitination;Regulation of TP53 Activity through Phosphorylation;Regulation of TP53 Activity through Methylation;Regulation of TP53 Activity;Trafficking of AMPA receptors;Tryptophan degradation;Transcriptional Regulation by TP53;Glutamate binding, activation of AMPA receptors and synaptic plasticity;Neurotransmitter receptors and postsynaptic signal transmission;Transmission across Chemical Synapses;Direct p53 effectors;Constitutive Signaling by AKT1 E17K in Cancer;PI3K/AKT Signaling in Cancer;Cell Cycle;AKT phosphorylates targets in the cytosol;Intracellular signaling by second messengers;Diseases of signal transduction;Validated transcriptional targets of deltaNp63 isoforms;Regulation of Androgen receptor activity;Sumoylation by RanBP2 regulates transcriptional repression;ATM pathway;ATR signaling pathway;p53 pathway (Consensus)

Recessive Scores

• pRec: 0.640

Intolerance Scores

• loftool: 0.317
• rvis_EVS: -0.52
• rvis_percentile_EVS: 21.2

Haploinsufficiency Scores

• pHI: 0.972
• hipred: Y
• hipred_score: 0.825
• ghis: 0.619

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.999

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Mdm2
• Phenotype: digestive/alimentary phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); limbs/digits/tail phenotype; skeleton phenotype; renal/urinary system phenotype; immune system phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; pigmentation phenotype; neoplasm; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); growth/size/body region phenotype; reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); craniofacial phenotype; muscle phenotype; homeostasis/metabolism phenotype; cellular phenotype; endocrine/exocrine gland phenotype

Zebrafish Information Network

• Gene name: mdm2
• Affected structure: renal capsular space
• Phenotype tag: abnormal
• Phenotype quality: dilated

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;blood vessel development;blood vessel remodeling;regulation of heart rate;atrioventricular valve morphogenesis;endocardial cushion morphogenesis;ventricular septum development;atrial septum development;ubiquitin-dependent protein catabolic process;DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest;traversing start control point of mitotic cell cycle;positive regulation of cell population proliferation;response to iron ion;positive regulation of gene expression;negative regulation of protein processing;negative regulation of neuron projection development;viral process;protein ubiquitination;protein deubiquitination;protein sumoylation;peptidyl-lysine modification;protein destabilization;response to magnesium ion;positive regulation of proteasomal ubiquitin-dependent protein catabolic process;protein localization to nucleus;transcription factor catabolic process;regulation of protein catabolic process;response to cocaine;negative regulation of cysteine-type endopeptidase activity involved in apoptotic process;response to morphine;negative regulation of DNA damage response, signal transduction by p53 class mediator;establishment of protein localization;response to ether;negative regulation of transcription, DNA-templated;positive regulation of mitotic cell cycle;response to antibiotic;positive regulation of protein export from nucleus;response to steroid hormone;proteolysis involved in cellular protein catabolic process;protein autoubiquitination;cardiac septum morphogenesis;protein-containing complex assembly;cellular response to hydrogen peroxide;negative regulation of cell cycle arrest;cellular response to vitamin B1;cellular response to alkaloid;cellular response to growth factor stimulus;cellular response to peptide hormone stimulus;cellular response to estrogen stimulus;cellular response to hypoxia;cellular response to gamma radiation;cellular response to UV-C;cellular response to actinomycin D;regulation of signal transduction by p53 class mediator;negative regulation of signal transduction by p53 class mediator;negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator;response to formaldehyde;positive regulation of vascular smooth muscle cell proliferation;positive regulation of vascular associated smooth muscle cell migration;amyloid fibril formation;response to water-immersion restraint stress
• Cellular component: nucleus;nucleoplasm;nucleolus;cytoplasm;cytosol;plasma membrane;nuclear body;endocytic vesicle membrane;protein-containing complex;synapse
• Molecular function: p53 binding;ubiquitin-protein transferase activity;protein binding;5S rRNA binding;zinc ion binding;ligase activity;SUMO transferase activity;enzyme binding;protein domain specific binding;ubiquitin protein ligase binding;receptor serine/threonine kinase binding;identical protein binding;peroxisome proliferator activated receptor binding;ribonucleoprotein complex binding;ubiquitin binding;protein N-terminus binding;ubiquitin protein ligase activity;NEDD8 ligase activity;scaffold protein binding;disordered domain specific binding